Pyrimidine Carboxylic Acid Derivatives and Use Thereof

Abstract

The present application relates to pyrimidinecarboxylic acid derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular disorders, in particular dyslipidaemias and arteriosclerosis.

1 . Compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 A represents CH 2  or O, 
 R 1  represents halogen, cyano or (C 1 -C 4 )-alkyl, 
 R 2  represents a substituent selected from the group consisting of halogen, cyano, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine, or represents a group of the formula —NR 7 —C(═O)—R 8 , in which
 R 7  represents hydrogen or (C 1 -C 6 )-alkyl 
 and 
 R 8  represents hydrogen, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy, 
 
 n represents the number 0, 1, 2 or 3,
 where in the case that the substituent R 2  is present more than once its meanings may be identical or different, 
 
 R 3  represents hydrogen, fluorine or chlorine, 
 R 4  represents hydrogen, halogen, nitro, cyano, amino, trifluoromethyl, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy, 
 R 5  and R 6  are identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine, represent amino, mono- or di-(C 1 -C 6 )-alkylamino, a 4- to 7-membered heterocycle which is attached via an N atom, or represent a group of the formula —NR 9 —C(═O)—R 10 , in which
 R 9  represents hydrogen or (C 1 -C 6 )-alkyl 
 and 
 R 10  represents hydrogen, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy, 
 
 
       and
 Z represents hydrogen or (C 1 -C 4 )-alkyl, 
 
       and its salts, solvates and solvates of the salts, 
       for the treatment and/or prophylaxis of diseases. 
     
     
         2 . Compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       in which
 A represents CH 2  or O, 
 R 1  represents halogen, cyano or (C 1 -C 4 )-alkyl, 
 R 2  represents a substituent selected from the group consisting of halogen, cyano, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine, or represents a group of the formula —NR 7 —C(═O)—R 8 , in which
 R 7  represents hydrogen or (C 1 -C 6 )-alkyl 
 and 
 R 8  represents hydrogen, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy, 
 
 n represents the number 0, 1, 2 or 3,
 where in the case that the substituent R 2  is present more than once its meanings may be identical or different, 
 
 R 3  represents hydrogen, fluorine or chlorine, 
 R 4  represents hydrogen, halogen, nitro, cyano, amino, trifluoromethyl, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy, 
 R 5  and R 6  are identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine, represent amino, mono- or di-(C 1 -C 6 )-alkylamino, a 4- to 7-membered heterocycle which is attached via an N atom, or represent a group of the formula —NR 9 —C(═O)—R 10 , in which
 R 9  represents hydrogen or (C 1 -C 6 )-alkyl 
 and 
 R 10  represents hydrogen, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy, 
 
 
       and
 Z represents hydrogen or (C 1 -C 4 )-alkyl, 
 
       and its salts, solvates and solvates of the salts, 
       except for the compounds ethyl 4-(2-methylphenoxy)-2-phenylpyrimidine-5-carboxylate, 4-(2-methylphenoxy)-2-phenylpyrimidine-5-carboxylic acid, ethyl 4-(2,3-dimethylphenoxy)-2-phenylpyrimidine-5-carboxylate, 4-(2,3-dimethylphenoxy)-2-phenylpyrimidine-5-carboxylic acid, ethyl 2-phenyl-4-(2,4,5-trichlorophenoxy)pyrimidine-5-carboxylate and 2-phenyl-4-(2,4,5-trichlorophenoxy)pyrimidine-5-carboxylic acid. 
     
     
         3 . Compound of the formula (I) according to  claim 2 , in which
 A represents CH 2  or O,   R 1  represents halogen, cyano or (C 1 -C 4 )-alkyl,   R 2  represents a substituent selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine,   n represents the number 0, 1, 2 or 3,
 where in the case that the substituent R 2  is present more than once its meanings may be identical or different, 
   R 3  represents hydrogen, fluorine or chlorine,   R 4  represents hydrogen, halogen, cyano, trifluoromethyl, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,   R 5  and R 6  are identical or different and independently of one another represent hydrogen, halogen, nitro, cyano, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy in which alkyl and alkoxy for their part may be mono- or polysubstituted by fluorine, or represent amino, mono- or di-(C 1 -C 4 )-alkylamino,   
       and
 Z represents hydrogen, methyl or ethyl, 
 
       where at least one of the radicals R 3 , R 4 , R 5  and R 6  is different from hydrogen, 
       and its salts, solvates and solvates of the salts. 
     
     
         4 . Compound of the formula (I) according to  claim 2  or  3  in which
 A represents O,   R 1  represents fluorine, chlorine, bromine, cyano or methyl,   R 2  represents a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and trifluoromethoxy,   n represents the number 0, 1, 2 or 3,
 where in the case that the substituent R 2  is present more than once its meanings may be identical or different, 
   R 3  represents hydrogen or fluorine,   R 4  represents hydrogen, fluorine, chlorine, trifluoromethyl or methyl,   R 5  and R 6  are identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, nitro, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy or amino,   
       and
 Z represents hydrogen, 
 
       where at least one of the radicals R 3 , R 4 , R 5  and R 6  is different from hydrogen, 
       and its salts, solvates and solvates of the salts. 
     
     
         5 . Process for preparing a compound of the formula (I) as defined in  claims 1  to  4  in which
 A represents O, characterized in that compounds of the formula (II)   
       
         
           
           
               
               
           
         
       
       in which R 3 , R 4 , R 5  and R 6  are each as defined in  claims 1  to 4 and
 Z 1  represents (C 1 -C 4 )-alkyl 
 
       and
 X represents a suitable leaving group, such as, for example, halogen, in particular chlorine, 
 
       are reacted in an inert solvent in the presence of a base with a compound of the formula (III) 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2  and n are each as defined in  claims 1  to  4 , 
       to give compounds of the formula (I-A) 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1  and n are each as defined above, 
       and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-B) 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and n are each as defined above 
       and the compounds of the formulae (I-A) and (I-B) are, if appropriate, converted into their solvates, salts and/or solvates of the salts using the appropriate (i) solvents and/or (ii) bases or acids. 
     
     
         6 . Process for preparing a compound of the formula (I) as defined in  claims 1  to  3  in which A represents CH 2 , characterized in that either
 [A] compounds of the formula (VIII)   
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and n are each as defined in  claims 1  to  3  and 
           Z 1  represents (C 1 -C 4 )-alkyl, 
           are reacted with a compound of the formula (IX) 
         
       
       
         
           
           
               
               
           
         
         
           to give compounds of the formula (X) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2 , n and Z 1  are each as defined above 
           and then reacted in an inert solvent in the presence of a base with an amidine of the formula (V) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 3 , R 4 , R 5  and R 6  are each as defined in  claims 1  to  3 , 
           to give compounds of the formula (I-C) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1  and n are each as defined above 
         
         or 
         [B] compounds of the formula (XI) 
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and n are each as defined in  claims 1  to  3   
           are converted into the organotin compounds of the formula (XII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2  and n are each as defined above 
           and subsequently coupled in an inert solvent in the presence of a suitable palladium catalyst with a compound of the formula (II) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 3 , R 4 , R 5  and R 6  are each as defined in  claims 1  to  3  and Z 1  represents (C 1 -C 4 )-alkyl 
           and 
           X represents a suitable leaving group, such as, for example, halogen, in particular chlorine, 
           to give compounds of the formula (I-C) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1  and n are each as defined above 
         
         and the resulting compounds of the formula (I-C) are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-D) 
       
       
         
           
           
               
               
           
         
         in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and n are each as defined above and the compounds of the formulae (I-C) and (I-D) are, if appropriate, converted into their solvates, salts and/or solvates of the salts using the appropriate (i) solvents and/or (ii) bases or acids. 
       
     
     
         7 . Compound as defined in any of  claims 2  to  4  for the treatment and/or prophylaxis of diseases. 
     
     
         8 . Use of a compound as defined in any of  claims 1  to  4  for preparing a medicament for the treatment and/or prevention of dyslipidaemias and arteriosclerosis. 
     
     
         9 . Medicament, comprising a compound as defined in any of  claims 1  to  4  in combination with an inert non-toxic pharmaceutically suitable auxiliary. 
     
     
         10 . Medicament, comprising a compound as defined in any of  claims 1  to  4  in combination with a further active compound selected from the group consisting of CETP inhibitors, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, fibrates, niacin, lipase inhibitors, PPAR-γ and/or PPAR-δ agonists, thyroid hormones and/or thyroid mimetics, polymeric bile acid adsorbers, bile acid absorption inhibitors, antioxidants, cannabinoid receptor 1 antagonists, insulin and insulin derivatives, antidiabetics, calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, diuretics, platelet aggregation inhibitors and anticoagulants. 
     
     
         11 . Medicament according to  claim 9  or  10  for the treatment and/or prevent of dyslipidaemias and arteriosclerosis. 
     
     
         12 . Method for the treatment and/or prevention of dyslipidaemias and arteriosclerosis in humans and animals by adminstering an effective amount of at least one compound as defined in any of  claims 1  to  4  or of a medicament as defined in any of  claims 9  to  11 .